ANDAs impurities in drug substances - Pharmanet

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Draft-Not for ImplementationAttachment IImpurities Decision Tree(Generic Drugs)L1Decrease impurity levelbelow thresholdYesAbove ThresholdNoQualifiedL2Decrease belowthresholdNoYesStructure elucidated?YesNoIs the impurityobserved in theinnovator’s drugproduct and at asimilar level?No* Toxicity documented andsufficient?YesL3aNo• Compliance with a USP drugsubstance specification foran identified impurity?YesNoL3bDecrease belowthresholdNo• Is the impurity observed inthe innovator’s drug productand at a similar level?YesQualifiedNoL3cNo• If at a higher level, or a newimpurity is detected…is it qualified from thescientific literature?YesNoYesL4NoRelated to others withknown toxicity?YesAcceptableJustification**NoL5Decrease belowthresholdNoQualified by a simplebattery ofgenotoxicity tests?YesQualifiedNoL6NoQualified by additionaltoxicity testing?YesQualifiedbut not 505(j)* Generic Drug Pathway** e.g., qualified by QSARJ:\!GUIDANC\2452DFT.WPDJuly 21, 199812
Draft-Not for ImplementationAttachment IIICH Decision Tree for Safety StudiesDecrease impurity levelbelow thresholdYesAbove ThresholdNoQualifiedYesNoStructure elucidated?YesYesToxicity documented andsufficient?NoRelated to others withknown toxicity?YesAcceptablejustification?NoConsider patient populationand duration of useNoYesQualifiedConsider need for:1. Genotoxicity studies (point mutation, chromosomal aberration) a2. General toxicity studies (one species, min. 14 days, max. 90 days) b3. Other specific toxicity endpoint, as appropriateAdverse EffectsYesNoConsider additional testingor removal of impurityQualifiedaIf considered desirable, a minimum screen for genotoxic potential should be conducted. A study to detect pointmutations and one to detect chromosomal aberrations, both in vitro, are seen as an acceptable minimum screen.bFor NDAs, if general toxicity studies are desirable, study(ies) should be designed to allow comparison ofunqualified to qualified material. The study duration should be based on available relevant information andperformed in the species most likely to maximize the potential to detect the toxicity of an impurity. In general, aminimum duration of 14 days and a maximum duration of 90 days will be acceptable.J:\!GUIDANC\2452DFT.WPDJuly 21, 199813
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ANDAs impurities in drug substances - Pharmanet

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